1. Field of the Invention
This invention relates to isoquinoline compounds, in particular ones binding to nucleic acids and having anti-bacterial properties, and methods for their use.
2. Description of Related Art
A number of naturally occurring or synthetic compounds bind to double stranded nucleic acid, especially double stranded DNA (xe2x80x9cdsDNAxe2x80x9d). Some bind to the major groove, while others bind to the minor groove. Still others intercalate between adjacent base pairs. Combination binding modes are known, in which a compound has binding interactions with more than one nucleic acid site.
It has been proposed to use dsDNA binding compounds to regulate the expression of genes for medical purposes. If a disease is characterized by the overexpression or undesired expression of a gene (e.g., an oncogene), in principle the disease can be treated by suppressing wholly or partially the gene""s expression via the binding of a compound to the gene or a promoter site thereof and interfering with transcription. Infections by pathogens such as fungi, bacteria, and viruses can be treated with compounds that interfere with the expression of genes essential for the pathogen""s proliferation. Or, in a disease characterized by non- or under-expression of a beneficial gene, the expression of the beneficial gene can be up-regulated with a compound that binds to the binding site of a repressor, displacing the repressor.
The natural products distamycin and netropsin represent a class of DNA-binding compounds that has been studied over the years: 
Structurally, distamycin and netropsin are heteroaromatic polyamides, having as their core structural motif N-methylpyrrole carboxamide residues. They bind to the minor groove, their crescent molecular shapes providing a conformational fit within the groove. The binding occurs with a preference for A,T rich dsDNA tracts.
Many heteroaromatic polyamides have been synthesized elaborating on the distamycin/netropsin motif, with the objective of enhancing or varying biological activity, increasing binding affinity to dsDNA, and/or improving specificity in base pair sequence recognition. See Bailly et al., Bioconjugate Chemistry 1998, 9 (5), 513-538, and Neidle, Nat. Prod. Rep. 2001, 18, 291-309. The use of synthetic heteroaromatic polyamides in therapeutics has been proposed, for example, in Dervan et al., U.S. Pat. No. 5,998,140 (1999); Dervan et al., WO 00/15209 (2000); Dervan, WO 00/15773 (2000); and Gottesfeld et al., WO 98/35702 (1998).
This invention provides isoquinoline compounds having the formula 
including the pharmaceutically acceptable salts thereof.
Each R1 is independently H, F, Cl, Br, I, CN, OH, NO2, NH2, a substituted or unsubstituted (C1-C12)alkyl group, a substituted or unsubstituted (C1-C12)alkoxy group, or a substituted or unsubstituted (C1-C12)heteroalkyl group.
Each Y is independently a branched or unbranched, substituted or unsubstituted (C1-C5)alkylene group or a substituted or unsubstituted, aromatic or heteroaromatic ring system, wherein the ring system has a 5- or 6-member aromatic or heteroaromatic ring or fused 6,6 or 6,5 aromatic or heteroaromatic rings, with the proviso that at least one Y is a substituted or unsubstituted aromatic or heteroaromatic ring system. Preferably, at least one Y is a 5- or 6-member heteroaromatic ring. More preferably, Y in the moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 immediately adjacent to 
is a 5- or 6-member heteroaromatic ring.
Subscript m is an integer from 1 to 25, inclusive, preferably from 1 to 6, more preferably from 2 to 4.
Z is either O or N, with n being 1 if Z is O and 2 if Z is N.
Each R2 is independently H, a substituted or unsubstituted (C1-C12)alkyl group, or a substituted or unsubstituted (C1-C12)heteroalkyl group.
Compound (I) has a basic group having a pKb of 12 or less or a quaternized nitrogen group.
Preferably, each moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 is independently selected from the group consisting of:
(a) moieties M1 having the formula 
wherein one of X1, X2, and X3 is a ring vertex selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NR2xe2x80x94, and the other two of X1, X2, and X3 are ring vertices selected from the group consisting of xe2x95x90Nxe2x80x94 and xe2x95x90CR1xe2x80x94;
(b) moieties M2 having the formula 
wherein x is 0 or 1 and each R15 is independently H, OH, NH2, or F;
(c) moieties M3 having the formula 
wherein each L is independently a divalent moiety separating xe2x80x94NHxe2x80x94 and xe2x80x94(Cxe2x95x90O)xe2x80x94 by 3 or 4 atoms; and
(d) moieties M4 having the formula 
Preferably, at least one moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 is a moiety M1. More preferably, the moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 immediately adjacent to the residue 
is a moiety M1.
In the preceding formulae, R1 and R2 are as previously defined.
Preferably, R1 is hydrogen, halogen (F, Cl, Br, or I), a (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like, a (C1-C5)alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like, hydroxy, or cyano. Preferably, each R2 is H or a (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like.